review - accessdata.fda.gov · erd 18- 106, section 6.3.1 functional require m ents sid 10 needle...

CENTER FOR DRUG EVALUATION AND

RESEARCH

APPLICATION NUMBER:

213224Orig1s000

PRODUCT QUALITY REVIEW(S)

OFFICE OF PRODUCT EVALUATION AND QUALITY OFFICE OF HEALTH TECHNOLOGY 3

DIVISION OF DRUG DELIVERY, GENERAL HOSPITAL & HUMAN FACTORS INTERCENTER CONSULT MEMORANDUM

Date 12/16/2019 To: Meghna Jairath Requesting Center/Office:

CDER/OND Clinical Review Division:

DMEP

From Peter Petrochenko OPEQ/OHT3/DHT3C

Through (Team) Rumi Young, Team Lead, Injection Team OPEQ/OHT3/DHT3C

Through (Division) *Optional

CPT Alan Stevens, Assistant Director OPEQ/OHT3/DHT3C

Subject NDA 213224, Octreotide Acetate Injection ICC 1900319 ICCR2019-04781

Recommendation Filing Recommendation Date: 6/7/2019 CDRH did not provide a Filing Recommendation Device Constituent Parts of the Combination Product are acceptable for Filing. Device Constituents Parts of the Combination Product are Acceptable for Filing with

Information requests for the 74-Day Letter, See Appendix A Device Constituents Parts of the Combination Product are Not Acceptable for Filing - See

Section 5.4 for Deficiencies Mid-Cycle Recommendation Date: 8/26/2019

CDRH did not provide a Mid-Cycle Recommendation CDRH has no approvability issues at this time. CDRH has additional Information Requests, See Appendix A CDRH has Major Deficiencies that may present an approvability issue, See Appendix A.

Final Recommendation Date: 1/14/2020 Device Constituent Parts of the Combination Product are Approvable. Device Constituent Parts of the Combination Product are Approvable with Post-Market

Requirements/Commitments, See Section 2.3 Device Constituent Parts of the Combination Product are Not Approvable - See Section 2.2 for

Complete Response Deficiencies

Digital Signature Concurrence Table

Reviewer Team Lead (TL) Division (*Optional)

Reference ID: 4546706Reference ID: 4553199

ICC 1900319 NDA 213224, Octreotide Acetate Injection Sun Pharmaceutical Industries Limited

1. SUBMISSION OVERVIEW Submission Information Submission Number NDA 213224 Sponsor Sun Pharmaceutical Industries Limited Drug/Biologic Octreotide Acetate Injection

Indications for Use

For the treatment of acromegaly, severe diarrhea/flushing episodes associated with metastatic carcinoid tumors, and profuse watery diarrhea associated with Vasoactive Intestinal Peptide (VIP) secreting tumors

Device Constituent Pen-Injector Related Files n/a

Review Team Lead Device Reviewer Peter Petrochenko

2. EXECUTIVE SUMMARY AND RECOMMENDATION

CDRH recommends the combination product is: Approvable – the device constituent of the combination product is approvable for the proposed indication. Approvable with PMC or PMR, See Section 2.3

Not Acceptable – the device constituent of the combination product is not approvable for the proposed indication. We have Major Deficiencies to convey, see Section 2.2.

Section Adequate

Reviewer Notes Yes No NA

Device Description X Labeling X Design Controls X Risk Analysis X Design Verification X Injection force of the final finished device after

stability/shipping was provided interactively. Previously the Sponsor wanted to leverage break loose and glide force of the plunger/cartridge only (which includes one out of specification result in the 18-months study) in place of injection force of the completely assembled device. Sponsor agreed to add injection force of the final finished device at release, investigation any failures and reject batches per their sampling plan.



Injection time was not provided; however, the justification is acceptable since this is a manually driven injector with different doses.

Consultant Discipline Reviews X Clinical Validation X Human Factors Validation X Reviewed by CDER/OND/DMEPA Facilities & Quality Systems X Reviewed by CDRH/OC

2.1. Comments to the Review Team CDRH does not have any further comments to convey to the review team. CDRH has the following comments to convey to the review team:

Comment #1: While the sponsor addressed the cartridge glide force failures observed over stability, we recommend CDER OPQ to

sampling plan/batch rejection) and they added injection force testing of the final finished device to their release testing program.

2.2. Complete Response Deficiencies There are no outstanding unresolved information requests, therefore CDRH does not have any outstanding

deficiencies. The following outstanding unresolved information requests should be communicated to the Sponsor as part

of the CR Letter:

2.3. Recommended Post-Market Commitments/Requirements

assess if this impacts their review of the processes of the cartridge since the root cause of the observed high forces was due to the cartridge. CDRH ultimately accepted the response and observed failures since their process detected the failures, their follow-up quality activities were adequate (root cause investigation,

(b) (4)

(b) (4)

CDRH has Post-Market Commitments or Requirements CDRH does not have Post-Market Commitments or Requirements



TABLE OF CONTENTS

1. SUBMISSION OVERVIEW........................................................................................................................... 2 2. EXECUTIVE SUMMARY AND RECOMMENDATION............................................................................ 2

2.1. Comments to the Review Team ............................................................................................................... 3 2.2. Complete Response Deficiencies ............................................................................................................. 3 2.3. Recommended Post-Market Commitments/Requirements ...................................................................... 3

3. PURPOSE/BACKGROUND .......................................................................................................................... 6 3.1. Scope ........................................................................................................................................................ 6 3.2. Prior Interactions ...................................................................................................................................... 6

3.2.1. Related Files...................................................................................................................................... 6 3.3. Indications for Use ................................................................................................................................... 6 3.4. Materials Reviewed.................................................................................................................................. 6

4. DEVICE DESCRIPTION................................................................................................................................ 7 4.1. Device Description................................................................................................................................... 7 4.2. Steps for Using the Device..................................................................................................................... 10 4.3. Device Description Conclusion.............................................................................................................. 10 4.4. Facilities Information ............................................................................................................................. 11 4.5. Quality System Documentation Triage Checklist .................................................................................. 11

5. LABELING ................................................................................................................................................... 11 5.1. General Labeling Review....................................................................................................................... 11 5.2. Device Specific Labeling Review.......................................................................................................... 12 5.3. Clinical Labeling Review....................................................................................................................... 12 5.4. Labeling Review Conclusion ................................................................................................................. 12

6. DESIGN CONTROL SUMMARY............................................................................................................... 13 6.1. Summary of Design Control Activities.................................................................................................. 13 6.2. Design Controls Information Requests and Responses.......................................................................... 13

6.2.1. IR #1................................................................................................................................................ 13 6.3. Applicable Standards and Guidance Documents ................................................................................... 22 6.4. Design Control Review Conclusion....................................................................................................... 22

7. RISK ANALYSIS ......................................................................................................................................... 24 7.1. Risk Management Plan........................................................................................................................... 24 7.2. Hazard Analysis and Risk Summary Report.......................................................................................... 24 7.3. Risk Analysis Review Conclusion ......................................................................................................... 26

8. DESIGN VERIFICATION REVIEW........................................................................................................... 29 8.1. Performance/Engineering Verification .................................................................................................. 29

8.1.1. Essential Performance Requirement Evaluation............................................................................. 29 8.1.2. Verification of Design Inputs Evaluation ....................................................................................... 33 8.1.3. Evaluation of Test Methods ............................................................................................................ 34

8.2. Design Verification Review Conclusion ................................................................................................ 37 8.3. Discipline Specific Sub-Consulted Review Summary........................................................................... 39

9. CLINICAL VALIDATION REVIEW .......................................................................................................... 39 9.1. Review of Clinical Studies Clinical Studies .......................................................................................... 39

10. HUMAN FACTORS VALIDATION REVIEW....................................................................................... 39 11. FACILITIES & QUALITY SYSTEMS (Deferred to CDRH/OC)............................................................ 39

11.1. Facility Inspection Report Review ..................................................................................................... 39



11.2. Quality Systems Documentation Review........................................................................................... 40 11.3. Control Strategy Review .................................................................................................................... 40 11.4. Facilities & Quality Systems Review Conclusion (Deferred to OC) ................................................. 41

12. APPENDIX A (INFORMATION REQUESTS) ....................................................................................... 42 12.1. Mid-Cycle Information Requests ....................................................................................................... 42 12.2. Interactive Information Requests........................................................................................................ 43

12.2.1. Interactive Information Requests sent on 12/17/2019................................................................. 43 12.2.2. Interactive Information Requests sent on 1/7/2020..................................................................... 45



3. PURPOSE/BACKGROUND 3.1. Scope Sun Pharmaceutical Industries Limited is requesting approval of Octreotide Acetate Injection. The device constituent of the combination product is a Pen-Injector.

CDER/OND has requested the following consult for review of the device constituent of the combination product: please review the new NDA

The goal of this memo is to provide a recommendation of the approvability of the device constituent of the combination product. This review will cover the following review areas:

- Device Performance - Biocompatibility - Risk Assessment - Labeling pertaining to the device - Design controls

This review will not cover the following review areas: - Human Factors (deferred to DMEPA) - Facilities and Compliance (Separate CDRH OC Consult) - Fluid path extractables leachables - Drug compatibility

The original review division will be responsible for the decision regarding the overall safety and effectiveness for approvability of the combination product.

3.2. Prior Interactions None

3.2.1. Related Files N/A

3.3. Indications for Use Combination Product Indications for Use

Octreotide Acetate Injection

For the treatment of acromegaly, severe diarrhea/flushing episodes associated with metastatic carcinoid tumors, and profuse watery diarrhea associated with Vasoactive Intestinal Peptide (VIP) secreting tumors

Pen-Injector Delivery of the Drug Product

3.4. Materials Reviewed Materials Reviewed All files in 3.2.P.5 and 3.2.P.7 Response to IRs



4. DEVICE DESCRIPTION 4.1. Device Description

Octreotide Acetate Injection, 2.5 mg/mL, is filled in 3 mL colorless USP(b) (4)

glass cartridges with 10 mm gray rubber plunger stopper and combination seal (cream inner and gray outer). One filled and

(b) (4)

sealed cartridge of Octreotide Acetate Injection, 2.5 mg/mL, packed in one transparent cartridge holder and assembled with the help of blue body subassembly (dark blue button and white dose set knob) and light blue cap for pen injector.

(b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4) (b) (4)

Changes from Wave 1 to Wave 2, in outer appearance of the fully assembled device are provided below in image 1.0:


(b) (4)


(b) (4)

(b) (4)

(b) (4)

(b) (4)

Table 3.0 Summarizes general characteristics of the injector: Table 3.0

Device Characteristics

Injector/Platform Name

Applicable (Yes /No)

Yes

Details Document reference

ERD 18-035, Section 1. Scope

Specifications Yes Customer Specifications and Design Input Specifications ERD 18-035

ERD 18-106

Injection tissue Yes Subcutaneous injection ERD 18-106, Section 4.1

Depth of Injection Yes Subcutaneous injection ERD 18-106, Section 4.1

Audible / visual feedback Yes

Dose increment indication is audible and dose set knob is visual, end of dose is also visible.

ERD 18-035, Section 5.2.1 Quality Criteria

ERD 18-106, Section 6.3.1 functional requirements, SID 12

Cap Removal Force Yes Its normal end user action. It comes under ergonomics/ comfortable to use.


ERD 18-106, Section 6.3.1 functional requirements SID 10, product functions ID 142-02, 142-03

Dose Accuracy Yes Volumetric Accuracy per ISO 11608-1


ERD 18-106, Section 6.3.1 functional requirements SID 3

Activation Force No Not Applicable Not Applicable

Visibility of medication / container dose

Yes Cartridge holder is transparent so that user can see medication inside glass cartridge

ERD 18-035, Section 3.1.4

ERD 18-106, Section 6.3.1 functional



requirements SID 14 Last dose specifications Yes It is as per ISO 11608-1:2014 ERD 18-106, Section 6.3.1 functional requirements SID 3, Input/Cust. Req. ID

251

Safety Features Yes Ergonomics and comfortable to use


Needle specifications, length and gauge Yes Needle 31 G x 5mm

ERD 18-035, Section 1. Scope ERD

18-106, Section 1.3.1

Connection type Yes User replaceable needles ERD 18-106, Section 1.0 Description

Conformance to applicable standards

Yes All applicable regulations, standards and guidance are mentioned

ERD 18-106, Section 5.0

Type of use (Single use, disposable, reusable)

Yes Multi use, disposable ERD 18-106, Section 1.0 Description

Intended user (e.g., self-administration, professional use, user characteristics and / or disease state that impact device use)

Yes Self-administration or administered by Health Care Provider ERD 18-106, Section 4.1 Intended Use

Injection mechanism (e.g., manual piston, spring, gas, etc.)

Yes Manual piston

ERD 18-035, Section 3.1.5.1


ERD 18-106, Section 2.1.2 Method of actuation, any Automated Functions

No No automated function Not Applicable

Residual Medication Yes

Total deliverable volume is minimum 2.8mL. However Cartridge would be filled with


Delivered Volume (for single dose or selectable volume range for multi-dose pens)

Yes

It is multi-use, variable dose, disposable pen where four doses would be delivered viz. i) 20 µL ii) 40 µL iii) 60 µ iv) 80 µ

ERD 18-106, Section 1.3.2 and 1.3.3

Drug Container Type Yes 3.0mL standard glass cartridge ERD 18-035, Section 1. Scope,


Dose Units of Measure (e.g., mL, Units, mg, increments, etc.) Yes

Dose marking is in mcg however delivery would be in corresponding µL as concentration of drug is 2500 µg/mL.

ERD 18-035, Section 3.1.3 System markings,


It can be administered at home or in

(b) (4)

(b) (4)



Environments of use, clinical environment. (b) (4)

ERD 18-106, Section 4.1.1.1 Storage conditions and Yes ERD 18-106, Section 4.1.1.2 expiry

Cartridge holder has dark colored Graduation marks / ERD 18-106, Section 1.3.3 system markings markings to show the position ofYes fill lines inside rubber stopper.

The fully assembled drug device combination product would be supplied to the end user. During first use, user will detach the cap, attach

ERD 18-035, Section 1. Scope ERD Preparation and the needle, prime the pen, set the Yes dose and insert the needle at administration 18-106, Section 2.0 injection site and deliver the dose as per instructions given in Instructions For Use (IFU). Fully assembled pen injector device is Complete Material

ERD 18-035, Section 1.0 scope, 3.1.1 composed of several composition of Yes components, sub-components Materials injector and sub-assemblies.

4.2. Steps for Using the Device

1. Pull off the pen cap. 2. Take a new needle and tear off the paper tab. Push the needle straight onto the pen and turn clockwise

until it is tight. Pull off the outer needle cover and keep it for later. 3. Prime the pen (if it is new). - Turn the dose set knob and set it to ‘’200’’. With the needle pointing up

push in the injection button all the way until it stops. Repeat this procedure until you see a stream. 4. Routine use (for every dose) - Attach a new needle. Turn the dose set knob to select the correct dose you

need to inject. - Insert the needle into selected injection site. Push and hold the injection button for 10 seconds. Then pull the needle from skin.

5. Put outer needle cover on needle. Unscrew and pull off needle and throw it away. 6. Replace the pen cap.

4.3. Device Description Conclusion

DEVICE DESCRIPTION REVIEW CONCLUSION Filing Deficiencies: Yes No N/A

Mid-Cycle Deficiencies: Yes No N/A

Final Deficiencies: Yes No N/A

Reviewer Comments

Device description and steps for use is acceptable. Additionally, the Sponsor has provided a direct side by side comparison of their device to the RLD device. CDRH sent Device Description Deficiencies or Interactive Review Questions to the Sponsor: Yes

No



4.4. Facilities Information NOTE: A separate consult is being done for compliance by OC.

4.5. Quality System Documentation Triage Checklist

NOTE: A separate consult is being done for compliance by OC.

5. LABELING 5.1. General Labeling Review The labeling, including the device constituent labeling, user guides, patient information, prescriber information and all other labeling materials provided for review were reviewed to meet the following general labeling guidelines as appropriate:

General Labeling Review Checklist Adequate? Yes No N/A Indications for Use or Intended Use; including use environment(s); route(s) of administration for infusion, and treatment population.

X

Drug name is visible on device constituent and packaging X Device/Combination Product Name and labeling is consistent with the type of device constituent

X

Prescriptive Statement/Symbol on device constituent X Warnings X Contraindications X Instructions for Use X Final Instructions for Use Validated through Human Factors

X

Electrical Safety Labeling/Symbols X EMC Labeling/Symbols X Software Version Labeling X MRI Labeling/Symbols X RF/Wireless Labeling/Symbols X

Reviewer Comments Labeling is adequate.



5.2. Device Specific Labeling Review

(b) (4)

Device Specific Labeling Review Checklist Adequate? Yes No N/A Labelled volume (Dose Markings) X

5.3. Clinical Labeling Review The following Clinical Labeling Review was completed by

Insert Consultant Name ; The full memo is located in Appendix B. The Lead Reviewer

Below is a summary of the review & recommendation: Clinical Labeling is reviewed by CDER Clinical team and Instructions for Use are reviewed by DMEPA. A cursory review was done by the Lead Reviewer and no issues were identified regarding device labeling specifically.

5.4. Labeling Review Conclusion

LABELING REVIEW CONCLUSION Filing Deficiencies: Yes No N/A



Reviewer Comments

CDRH sent Labeling Deficiencies or Interactive Review Questions to the Sponsor: Yes No

No Additional Information Requests – Finalize Labeling Review Section



6. DESIGN CONTROL SUMMARY 6.1. Summary of Design Control Activities

Risk Analysis Attributes Yes No N/A Risk analysis conducted on the combination product X Hazards adequately identified (e.g. FMEA, FTA, post-market data, etc.) X Mitigations are adequate to reduce risk to health X Version history demonstrates risk management throughout design / development activities

X

Design Inputs/Outputs Yes No N/A Design requirements / specifications document present (essential performance requirements included)

X

Design Verification / Validation Attributes Yes No N/A Validation of essential requirements covered by clinical and human factors testing X To-be-marketed device was used in the pivotal clinical trial X Bioequivalence Study utilized to-be-marketed device X (IR

resolved) Verification methods relevant to specific use conditions as described in design documents and labeling

X

Device reliability is acceptable to support the indications for use (i.e. emergency use combination product may require separate reliability study)

X

Traceability demonstrated for specifications to performance data X

6.2. Design Controls Information Requests and Responses 6.2.1. IR #1 1. In your Summary of Container Closure System, you provided a comparison between the “existing” and

“commercial” versions of the pen injector and stated that “there is some minor changes to the secondary packaging components between the exhibit and propose commercial pen injector.” More information is necessary to ensure this change does not affect device function. Please clarify whether the design change affected any internal and/or mechanical components and which version(s) were used for all applicable device testing including the provided batch analyses, stability, and all clinical studies. If the testing you have performed used different versions, please provide a complete justification for each modification and whether it is expected to affect device performance, specifically, whether essential performance requirements (Dose Accuracy, Activation/Break loose/Glide Forces, Needle Length/Gauge) and other performance requirements (Ex. cap removal force) are affected.

a. Additionally, your device description is only provided in the Summary of Container Closure System and is missing information on several device characteristics. This information is required to ensure the device functions safely and effectively in the intended environment of use. Please provide a complete device description of the final finished device you intend to market. In your description, be sure to include pictures and/or diagrams of internal device components. A complete device description should also include (following aspects should be selected only if they apply to your device): the Injector/Platform Name, Specifications, Injection tissue and depth of injection, Audible / visual feedback, Cap Removal Force, Dose Accuracy, Activation Force, Visibility of medication container/Dose, Last Dose Specifications and Safety Features, Needle Specifications (Length(s), Gauge(s)), Connection type, Conformance to applicable standards,



Type of Use (e.g. single use, disposable, reusable, other), Intended user (e.g., self-administration, professional use, user characteristics and / or disease state that impact device use), Injection mechanism (e.g., manual piston, spring, gas, etc.), Method of actuation, any Automated Functions, Residual Medication, Delivered Volume (for single dose or selectable volume range for multidose pens), Drug Container Type, Dose Units of Measure (e.g., mL, Units, mg, increments, etc.), Environments of use, Storage conditions and expiry, Graduation marks / fill lines, Preparation and administration (describe all that are applicable), Safety Features, Complete Material composition of injector, and other characteristics which may be applicable to your device. Please note if this information is provided elsewhere in the submission you may simply reference it.

Response:

Please note that comparison between existing and commercial pen components for Octreotide Acetate Injection, 2.5 mg/mL, 2.8 mL Pen Injector along with diagrams has been provided in section 3.2.P.7.1 of original NDA submission under leaf “Summary of Container Closure System” (page # 3 of 11).

Details of changes in internal as well as external pen components between the exhibit and proposed commercial pen injector are summarized in Attachment-1. Device supplier uses terminology ‘Wave 1’ for exhibit batch pen components and ‘Wave 2’ for pen components for commercial batches. These changes are implemented to make the delivery device more robust and better in look and feel and are not expected to affect device performance. As there is no design change with respect to functional performance of the device, the specifications for delivered dose volume, break loose and glide force remains same for both the versions. Also other performance requirements like cap removal force specifications are same for both the versions.

Information on version of device used for device testing is provided in Table 1.0 and Comparison of essential performance requirements is provided in Table 2.0

Table 1.0

Type of Analysis / Study Exhibit pen components (Wave1)

Commercial pen components (Wave2)

Stability Yes No Clinical (Bioequivalence) Yes No Design Verification Test including dose accuracy

Yes Yes

Human Factors Study (Formative) with straight cap

Yes No

Human Factors Study (Summative or validation) with straight cap

No Yes

Table 2.0

Essential Performance Requirements

Exhibit batch pen components Commercial pen components



Delivered dose volume i) 20 µ ii) 40 µ iii) 60 µ iv) 80 µL

i) 20 µL ii) 40 µL iii) 60 µL iv) 80 µL

Break loose force* Glide Force* Reference Design Verification Summary Report

ERD 6017-17-734-052 Revision 01

ERD 6017-17-734-173 Revision 03

Other Performance Requirements Cap removal force *Break loose and glide force test is conducted on primary containers (3.0mL standard glass cartridge). There is no change in primary containers for exhibit batch and commercial version of drug device combination product.

(b) (4) (b) (4)

(b) (4)

(b) (4)

Changes from Wave 1 to Wave 2, in outer appearance of the fully assembled device are provided below in image 1.0.

Image 1.0

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Design details and internal mechanical components for device are provided below in Image 2.0 and Image 3.0.

1 Page has been Withheld in Full as b4 (CCI/TS) immediately following this page



a. Please note that complete device description including functional specifications as well as external device compatibility, storage conditions, material details are provided in Customer Specification and Design Input Specifications (DIS) documents for both the versions of pen components. Please note that Customer Specification (page # 21 of 702) and Design Input Specifications (DIS) (page # 41 of 702) have already been provided in section 3.2.P.7 of original NDA submission under leaf “Component Specification and Test Data”.

Information on device characteristics, its applicability, brief details and document references are summarized in below table.

Table 3.0


Applicable (Yes /No) Details Document reference

Injector/Platform Name Yes Disposable Pen ERD 18-035, Section 1. Scope

Specifications Yes Customer Specifications and Design Input Specifications ERD 18-035

ERD 18-106

Injection tissue Yes Subcutaneous injection ERD 18-106, Section 4.1

Depth of Injection Yes Subcutaneous injection ERD 18-106, Section 4.1

Audible / visual feedback Yes

Dose increment indication is audible and dose set knob is visual, end of dose is also visible.


ERD 18-106, Section 6.3.1 functional requirements, SID 12

Cap Removal Force Yes Its normal end user action. It comes under ergonomics/ comfortable to use.


ERD 18-106, Section 6.3.1 functional requirements SID 10, product functions ID 142-02, 142-03

Dose Accuracy Yes Volumetric Accuracy per ISO 11608-1



Activation Force Yes Provided interactively (see IR section);

Provided interactively

Visibility of medication / container dose

Yes Cartridge holder is transparent so that user can see medication inside glass cartridge



(b) (4)

(b) (4)

(b) (4)

(b) (4)



Last dose specifications Yes It is as per ISO 11608-1:2014

ERD 18-106, Section 6.3.1 functional requirements SID 3, Input/Cust. Req. ID 251

Safety Features Yes Ergonomics and comfortable to use ERD 18-106, Section 6.3.1 functional requirements SID 10

Needle specifications, length and gauge

Yes Needle 31 G x 5mm ERD 18-035, Section 1. Scope


Device Applicable Details Document reference Characteristics (Yes /No)

Connection type Yes User replaceable needles ERD 18-106, Section 1.0 Description

All applicable regulations, Conformance to Yes standards and guidance are ERD 18-106, Section 5.0 applicable standards mentioned Type of use (Single use, disposable, Yes Multi use, disposable ERD 18-106, Section 1.0 Description reusable) Intended user (e.g., self-administration, professional use, Self-administration or user characteristics Yes administered by Health Care ERD 18-106, Section 4.1 Intended Use and / or disease state Provider that impact device use)

ERD 18-035, Section 3.1.5.1 Injection mechanism (e.g., manual piston, Yes Manual piston ERD 18-106, Section 1.0 spring, gas, etc.) ERD 18-106, Section 2.1.2

Method of actuation, any Automated No No automated function Not Applicable Functions

Total deliverable volume is

Residual Medication Yes ERD 18-106, Section 1.3.2

minimum 2.8mL.

(b) (4)

(b) (4)

(b) (4)

(b) (4)

It is multi-use, variable dose, Delivered Volume disposable pen where four doses (for single dose or would be delivered viz. selectable volume Yes i) 20 µL ERD 18-106, Section 1.3.2 and 1.3.3 range for multi-dose v) 40 µ pens) vi) 60 µ

vii)80 µ



Drug Container Type Yes 3.0mL standard glass cartridge ERD 18-035, Section 1. Scope,


Dose Units of Measure (e.g., mL, Units, mg, increments, etc.)

Yes

Dose marking is in mcg however delivery would be in corresponding µL as concentration of drug is 2500 µg/mL.

ERD 18-035, Section 3.1.3 System markings,



Applicable (Yes /No) Details Document reference

Environments of use, Storage conditions and expiry

Yes

It can be administered at home or in clinical environment. ERD 18-106, Section 4.1.1.1

ERD 18-106, Section 4.1.1.2

Graduation marks / fill lines Yes

Cartridge holder has dark coloured markings to show the position of inside rubber stopper.

ERD 18-106, Section 1.3.3 system markings

Preparation and administration Yes

The fully assembled drug device combination product would be supplied to the end user. During first use, user will detach the cap, attach the needle, prime the pen, set the dose and insert the needle at injection site and deliver the dose as per instructions given in Instructions For Use (IFU).

ERD 18-035, Section 1. Scope


Complete Material composition of injector

Yes

Fully assembled pen injector device is composed of several components, sub-components and sub-assemblies.

ERD 18-035, Section 1.0 scope, 3.1.1 Materials

(b) (4)(b) (4)

Reviewer Comments:

The deficiency requested the Sponsor to: clarify whether their design change affected any internal and/or mechanical components, clarify which version(s) were used for all applicable device testing, and provide a justification for each modification and whether it affected device performance. The Sponsor has replied that they used a ‘Wave 1’ version for exhibit batch pen components and ‘Wave 2’ for pen components for commercial batches. The Sponsor argues that changes in Wave 2 make the delivery device “more robust” and “better in look and feel” and do not affect performance. Table 1.0 in the response above shows that Wave 1 was used for the clinical BE study, stability testing, verification, and formative HF testing; while Wave 2 was also used for verification testing and summative HF. Table 2.0 shows that the verification test requirements are the same for both versions and that both versions had the same acceptance criteria. This bridges the Wave



1 to the Wave 2 device acceptably. The modifications are minor and do not appear to affect performance (main changes are pen cap shape, markings, etc.). The Sponsor additionally provided a more complete device description. This is acceptable.

The response above also mentions that activation force is not applicable. In this case it is not activation force, but injection force that is an essential performance requirement (discussed below)



Reviewer Comments The following IRs were sent and resolved as part of the review.

1. In your Summary of Container Closure System, you provided a comparison between the “existing” and “commercial” versions of the pen injector and stated that “there is some minor changes to the secondary packaging components between the exhibit and propose commercial pen injector.” Please clarify whether the design change affected any internal and/or mechanical components and which version(s) were used for all applicable device testing including the provided batch analyses, stability, and all clinical studies. If the testing you have performed used different versions, please provide a complete justification for each modification and whether it is expected to affect device performance, specifically, whether essential performance requirements (Dose Accuracy, Activation/Break loose/Glide Forces, Needle Length/Gauge) and other performance requirements (Ex. cap removal force) are affected.

a. Additionally, your device description is only provided in the Summary of Container Closure System and is missing information on several device characteristics. This information is required to ensure the device functions safely and effectively in the intended environment of use. Please provide a complete device description of the final finished device you intend to market. In your description, be sure to include pictures and/or diagrams of internal device components. A complete device description should also include (following aspects should be selected only if they apply to your device): the Injector/Platform Name, Specifications, Injection tissue and depth of injection, Audible / visual feedback, Cap Removal Force, Dose Accuracy, Activation Force, Visibility of medication container/Dose, Last Dose Specifications and Safety Features, Needle Specifications (Length(s), Gauge(s)), Connection type, Conformance to applicable standards, Type of Use (e.g. single use, disposable, reusable, other), Intended user (e.g., self-administration, professional use, user characteristics and / or disease state that impact device use), Injection mechanism (e.g., manual piston, spring, gas, etc.), Method of actuation, any Automated Functions, Residual Medication, Delivered Volume (for single dose or selectable volume range for multidose pens), Drug Container Type, Dose Units of Measure (e.g., mL, Units, mg, increments, etc.), Environments of use, Storage conditions and expiry, Graduation marks / fill lines, Preparation and administration (describe all that are applicable), Safety Features, Complete Material composition of injector, and other characteristics which may be applicable to your device. Please note if this information is provided elsewhere in the submission you may simply reference it.

2. Risk Analysis Documentation – Provide a risk analysis associated with the final finished combination product that is inclusive of risks associated with the device constituent parts of the combination product. Your risk analysis should include all identified risks, potential hazards that are apparent to your device, risk control measures and/or mitigation strategies, verification of risk control and/or mitigation measures, and the clinical acceptability of any residual risk associated with the device. You should outline the methods in which you identified the risks of the product within your risk analysis documentation (e.g. DFMEA, UFMEA, Fault Tree Analysis, etc.). Refer to recognized consensus standard ISO 14971 “Medical devices - Application of risk management to medical devices” or device specific Guidance for more details.

3. We acknowledge you have provided verification testing of your device in your submission. You did not provide a specification for Injection Time, although your labeling indicates a specific injection



time. Please provide a justification why you have not included injection time in your verification testing or release/stability/shipping testing. Alternatively provide Design Verification Documentation traced to the design inputs of the device constituent which applies to injection time. Ensure that you utilize test methods and preconditioning that simulate the intended use of your product. You should use and justify a statistically significant sample size for this verification testing. Provide valid justifications for the acceptability of any test results that do not pass its acceptance criteria.

a. Additionally, you have not clarified whether your verification testing was performed with the final to-be-marketed version of the device. As part of design verification, you should verify the EPRs with the to-be-marketed version of the device constituent and the intended biologic/drug product. However, if you plan to rely on verification testing conducted with a surrogate (or different device design) be sure to provide a scientific rationale for the acceptability of the surrogate for the intended biologic/drug product (i.e. fluid characteristics, viscosity, etc.). If available, results of stability / shelf-life testing may be provided if the to-be-marketed version of the device constituent and intended drug/biologic product are used.

6.3. Applicable Standards and Guidance Documents Generally Applicable Standards and Guidance Documents: Standard or Guidance Conformance (Y/N/NA) AAMI / ANSI / ISO 14971:2007/(R)2010 (Corrected 4 October 2007), medical devices - applications of risk management to medical devices

Y

Standard Practice for Performance Testing of Shipping Containers and Systems; ASTM D4169-09

Y

IEC 60601-1-2:2014 Y Guidance for Industry and FDA Staff: Current Good Manufacturing Practice Requirements for Combination Products (2017)

NA – OC consult

Mobile Medical Applications Guidance for Industry and Food and Drug Administration Staff (2015)

NA

Guidance for Industry and FDA Staff – Medical Devices with Sharps Injury Prevention Features (2005)

NA

Use of International Standard ISO 10993-1, Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process"

NA

Applying Human Factors and Usability Engineering to Medical Devices NA – DMEPA consult

Device Specific Standards and Guidance Documents

Standard or Guidance Recognized (Y/N/NA) Conformance

(Y/N/NA) Guidance for Industry and FDA Staff: Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products

NA Y

ISO 11608- 1:2014. Needle-based injection systems for medical use — Requirements and test methods — Part 1: Needle-based injection systems.

Y Y

6.4. Design Control Review Conclusion

DESIGN CONTROL REVIEW CONCLUSION Filing Deficiencies: Yes No N/A





Reviewer Comments

CDRH sent Design Control Deficiencies or Interactive Review Questions to the Sponsor: Yes No

Date Sent: Click or tap to enter a date.

Date/Sequence Received: Click or tap to enter a date.

Information Request #

1. We acknowledge you have provided verification testing of your device in your submission. You did not, however, provide a specification for Injection Time, although your labeling indicates a specific injection time. Please provide a justification why you have not included injection time in your verification testing or release/stability/shipping testing. Alternatively provide Design Verification Documentation traced to the design inputs of the device constituent which applies to injection time. Ensure that you utilize test methods and preconditioning that simulate the intended use of your product. You should use and justify a statistically significant sample size for this verification testing. Provide valid justifications for the acceptability of any test results that do not pass its acceptance criteria.

a. Additionally, you have not clarified whether your verification testing was performed with the final to-be-marketed version of the device. As part of design verification, you should verify the EPRs with the tobe-marketed version of the device constituent and the intended biologic/drug product. However, if you plan to rely on verification testing conducted with a surrogate (or different device design) be sure to provide a scientific rationale for the acceptability of the surrogate for the intended biologic/drug product (i.e. fluid characteristics, viscosity, etc.). If available, results of stability / shelf-life testing may be provided if the to-be-marketed version of the device constituent and intended drug/biologic product are used.

b. You have not provided a biocompatibility assessment of the device, including the material components, the manufacturing processes, the clinical use of the device including the intended anatomical location, and the frequency and duration of exposure. This information is required to ensure the device is safe. Please provide a justification or documentation to support the biocompatibility of your device constituent including test reports and protocols to ensure that the system components are biocompatible commensurate with the level and duration of patient contact. Refer to the FDA Guidance titled Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" – Guidance for Industry and Food and Drug Administration Staff



issued in June 2016 (https://www.fda.gov/media/85865/download) for more details.

Sponsor Response Addressed in Design verification section Reviewer Comments See section below Response Adequate: Yes No, See IR # Sent on Click or tap to enter a date.

7. RISK ANALYSIS 7.1. Risk Management Plan The Sponsor has developed a process FMEA, which was provided interactively. Additionally, the Sponsor analysed use errors in the formative/summative HF studies.

(b) (4)(b) (4)

(b) (4)(b) (4)supplies the customized pen injector and the Sponsor leveraged the dFMEA from (report was provided in 3.2.P.7. Component Specification and Data).

Risk Analysis Method Design failure modes and effects analysis (DFMEA) Application Failure Modes and Effects Analysis (AFMEA) or (UFMEA) – Part of Human Factors study Risk Management Summary Report (RMSR)

Application Failure Modes and Effects Analysis (AFMEA) or (UFMEA) – Part of Human Factors study Application Failure Modes and Effects Analysis (AFMEA) or (UFMEA) – Separate document

Process Failure Modes and Effects Analysis (PFMEA)

Latest Approval Date (b) (4)(b) (4) - (b) (4)(b) (4)LOA provided for MAF review

08 August 2017 Formative HF study

Conducted by (supplier)for the pen platform, provided in NDA (2018)

(b) (4)(b) (4)

13 March 2019 Summative HF study

07 September 2019 – Provided interactively (excerpt below) 21 September 2019 - Provided interactively (excerpt below)

Reviewer Comments The approach is acceptable and covers the requirements outlined in the initial IR to the Sponsor.

7.2. Hazard Analysis and Risk Summary Report

Sponsor’s uFMEA (AFMEA):



(b) (4)(b) (4)

(b) (4)(b) (4)

pFMEA describing the process, risks, and mitigations:

(b) (4)

)

(b) (4)

(b) (4)

)

(b) (4)



(b) (4)(b) (4) Risk Management Plan (leveraged for dFMEA). The report defines risk severity, residual risk evaluation, risk management activities, evaluation, reporting, etc. Excerpt shown below:

(b) (4)(b) (4)

Reviewer Comments The Sponsor’s risk management process leverages the design FMEA from the supplier, has a complete risk management plan, which is continuously applied during the cycle and additional risks, if identified, are reviewed and documented following the process described in the document submitted in the NDA by the Sponsor. In addition, the Sponsor has a risk management process for use risks and final assembly processes.

Disposable Pen life

(b) (4)

(b) (4)

(b) (4)

(b) (4)

7.3. Risk Analysis Review Conclusion

RISK ANALYSIS REVIEW CONCLUSION Filing Deficiencies: Yes No N/A



Reviewer Comments The risk analysis provided is sufficient. CDRH sent Risk Analysis Deficiencies or Interactive Review Questions to the Sponsor: Yes No



Information Request #

Risk Analysis Documentation – Provide a risk analysis associated with the final finished combination product that is inclusive of risks associated with the device constituent parts of the combination product. Your risk analysis should include all identified risks, potential hazards that are apparent to your device, risk control measures and/or mitigation strategies, verification of risk control and/or mitigation measures, and the clinical acceptability of any residual risk associated with the


(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4)

(b) (4)


device. You should outline the methods in which you identified the risks of the product within your risk analysis documentation (e.g. DFMEA, UFMEA, Fault Tree Analysis, etc.). Refer to recognized consensus standard ISO 14971 “Medical devices - Application of risk management to medical devices” or device specific Guidance for more details.

Sponsor Response Please note that as a part of human factor studies, Application Failure Modes and Effects Analysis (AFMEA) or User FMEA have been conducted which include risks associated with the device constituent part. This risk analysis included user tasks, critical task, potential use errors, clinical impact, risk severity, mitigations, study technique, measures and failure definition. Please note that human factors studies have been provided in section 5.3.5.4 of original NDA submission. Please note that recommendations from formative study were implemented before conducting summative validation study. Sun has also conducted and prepared separate AFMEA document to analyse the occurrence, severity and detection rating for each potential failure modes. Copy of this risk analysis have been provided herewith in Attachment 2. This analysis was conducted to identify, eliminate or minimize the impact of potential risks associated with end user of the final finished combination product. AFMEA concludes that Octreotide Acetate Injection, 2.5mg/mL, Pen Injector, 2.8mL is a low risk product and use errors will not cause serious consequences. All residual risks are mitigated and risk control measures already implemented.

Sun and device supplier has conducted risk analysis as per established ISO standard - ISO 14971 Medical devices - Application of risk management to medical devices.

Design Failure Modes and Effects Analysis (DFMEA) had also been conducted for the Disposable Liquid Pen (DLP) platform by device supplier,

. Same DLP platform is used to customize the Sun Pharma’s Octreotide pen. Sun Pharma has provided Letter of Authorisation (LOA) for MAF which contains DFMEA for DLP platform in section 1.4.1 of original NDA submission under leaf “DMF Letter of Authorization”. Also Risk Management Summary Report (RMSR) is part of original NDA submission, section 3.2.P.7.2 “Component Specification and Test Data” (page # 163 of 702). The RMSR provides a detailed overview on how residual risks are identified and managed for the system, including UFMEA, DFMEA and PFMEA. Risk benefit analyses are also included for all moderate (level 2) and higher risks.

Sun Pharma has also conducted Process Failure Modes and Effects Analysis (PFMEA) for Octreotide pen assembly and final packaging. PFMEA was conducted to identify potential failure modes, unwanted events, its root causes and measures to mitigating those during assembling of device constituent parts



with drug filled cartridges and then labelling and packaging. Copy of this risk assessment has been provided herewith in Attachment 3.

Below Table 4.0 provides information on methods used for conducting risk analysis for octerotide drug-device combination product and corresponding latest document approval date.

Table 4.0

Risk Analysis Method Latest Approval Date Design failure modes and effects analysis LOA provided for MAF-Application Failure Modes and Effects Analysis (AFMEA) or (UFMEA) – Part of Human 08 August 2017 (Formative HF study) Risk Management Summary Report (RMSR) 28 August 2018 Application Failure Modes and Effects Analysis (AFMEA) or (UFMEA) – Part of Human 13 March 2019 (Summative HF study) Application Failure Modes and Effects Analysis (AFMEA) or 07 September 2019 Process Failure Modes and Effects Analysis 21 September 2019

Reviewer Comments The deficiency requested the Sponsor to provide a risk analysis for the device constituent. The Sponsor stated that as part of human factor studies, Application Failure Modes and Effects Analysis (AFMEA) or User FMEA have been conducted which included risks associated with the device constituent part per ISO 14971. Design Failure Modes and Effects Analysis (dFMEA) had also been conducted for the Disposable Liquid Pen (DLP) platform by device supplier,

. The platform is used for this pen injector. The Sponsor has also provided Letter of Authorization (LOA) for MAF which contains the dFMEA. As part of their response, the Sponsor has also provided a Process Failure Modes and Effects Analysis (pFMEA) for the pen assembly and the final packaging. The pFMEA identified potential failure modes, unwanted events, root causes and mitigations during assembly, filling, labelling and packaging. The response is acceptable.

Response Adequate: Yes No, See IR # Sent on Click or tap to enter a date.

(b) (4) (b) (4)

(b) (4)

(b) (4) (b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4) (b) (4)


(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)


8. DESIGN VERIFICATION REVIEW 8.1. Performance/Engineering Verification

8.1.1. Essential Performance Requirement Evaluation Essential

Performance Requirement (Design

Input)

Specification (Design Output)

Verification Method Acceptable (Y/N)

Validation (Y/N)

Aging / Stability

(Y/N)

Shipping/ Transportation

(Y/N)

Delivered Dose Accuracy

Dose(mcg)=50 Dose volume=0.02mL ±

, K value = Pass if K greater than equal to . Dose(mcg)=100 Dose volume=0.04mL ±


, K value = Pass if K greater than equal to .

Y Finished Product -Analytical Test Procedure, pg. 44/50

Y (HF Validation for dose selector)

Y Y

Glide force Not more than Y Y Y- See IR 12.2.1-12.2.2 Y

Break-loose force Not more than Y Y Y – See IR 12.2.1-12.2.2 Y

Injection Time Not Provided Y (leveraged by break loose and glide force testing above) N/A N/A N/A

Injection Force (b) (4)(b) (4) Y Y Y Y



Reviewer Comment Injection time not provided – a justification or complete testing was required and requested with an IR. The Sponsor responded with a justification that injection time is not relevant since it is variable and since they additionally instruct the user to hold the injector for 10 seconds after visual/audio feedback that the injection is complete.

MAF , shown below, where the requirement is The Sponsor has not directly addressed dial torque of the dose selector or injection force of the button itself. Dial torque measurement, however, is

(b) (4)(b) (4) (b) (4)(b) (4) (b) (4)(b) (4)independent from the drug/cartridge, therefore, it can be leveraged from

The Sponsor makes the argument that injection force (pushing the button) is manual and is a direct push. The risk is present, however, of poorly

(b) (4)(b) (4)

manufactured components creating friction between the button and container (breakloose and glide forces were tested on the internal container only). However, BL/GF are very low ( (b) (4)(b) (4) and the interference from components or internal friction is not likely to raise the force much higher than

, which would need further testing.

To note, the MAF from (b) (4)(b) (4)

had data on the component alone (likely without aging or shipping) in the current version of MAF- (b) (4)(b) (4) , which has an UL of which is acceptable:

(b) (4)(b) (4)

(b) (4)

2 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page


(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)


Therefore, the device is showing possibility for out of spec glide force and injection force is not reported in the submission. The following IR was issued and resolved (See IR section 12.2.1 and 12.2.2)

8.1.2. Verification of Design Inputs Evaluation

Design Input

Design Output Verification Method Results/Deviations

Adequately Verified

(Y/N)

Validated through Clinical,

Human Factors or Other

Adequately Validated

(Y/N)

Delivered Dose Accuracy

Dose(mcg)=50 Dose volume=0.02mL ±

, K value = Pass if K greater than equal to Dose(mcg)=100 Dose volume=0.04mL ±


32 nos. of pens are taken. For a particular dose volume, 96 values of delivered dose need to be taken. Dose Delivered from Prefilled pen in mL = Weight of sample (g) delivered from Pen injector / Density of the sample

Calculate mean, standard deviation of dose delivered for 96 values of 32 pen injector for each dose setting (0.02mL, 0.04mL and 0.08mL).

Calculate the K Actual for each dose volume. Where “K” is tolerance limit factor as per ISO 11608- 1:2014.

K value: 8.167 K value: 9.800 K value: 8.727

Y Y Y

K value: 7.538 K value: 8.083 K value: 7.231

K value: 10.667 K value: 8.167

, K value = K value: Pass if K greater than equal to . Not more than

Pass if K Actual ≥ for each dose setting

5.529

Glide force Disassemble the pen and take out Mean: 4.943 N Y Y Y cartridge for testing. Mean: 4.941 N • Take 32 nos. of filled, crimped, stoppered cartridges

Mean: 5.287 N


(b) (4)(b) (4)


• Calculate the travel distance “X” in mm using scale from end of stopper touching the • Solution to bottom part of syringe as shown in picture & Set the parameter in machine…

Break-loose force

Not more than Disassemble the pen and take out cartridge for testing. • Take 32 nos. of filled, crimped, stoppered cartridges • Calculate the travel distance “X” in mm using scale from end of stopper touching the • Solution to bottom part of syringe as shown in picture & Set the parameter in machine…

Mean: 6.607 N Mean: 6.375 N Mean: 6.936 N

Y Y Y

Injection Time

Variable, based on dose; also variable depending on force exerted by user.

N/A N/A N – N/A Y Y

Reviewer Comment Injection time is not provided, which was an initial IR. The Sponsor has responded saying that injection time is not a necessary EPR for this device since the injection is manually driven and has different dose selections. This response was discussed above and is acceptable, primarily because the sponsor controls for break loose and glide forces.

8.1.3. Evaluation of Test Methods

Title: Annexure-V-Simulated Shipping Study Protocol Scope/Objective & Acceptance Criteria:

To check the effect of vibrations & shocks during transportation/manual handling on Pen functionality of Octreotide Acetate Injection, 2.5mg/mL, Pen Injector , 2.8mL packed in 2's thermoformed tray which is further packed in a carton. Such 12 cartons are packed in 3-Ply duplex box and such 8 numbers of 3-Ply duplex boxes are then packed in shipper (5-Ply corrugated box).



Methods

10.1 There should not be any damage to Package & component after performance of Vibration & drop testing. 10.2Physicochemical parameter of test sample should be within specification limit as per approved STP.

(b) (4)10.3Break out force should not be more than & Glide force should not be more than lON. Vibration study:

(b) (4)7.3 Packaging Development Scientist shall place the filled shippers on the vibration table. (Machine Model

System). Suitable provision is made at the center of the table in order to keep the shipper in upward orientation during the testing.

(b) (4)

(b) (4)

7.4 Perform the test at fixed frequency at RPM with amplitude of (b) (4)mm and Random mode of vibration for hours & report the visual observation.

Drop test study: 7.5 Packaging Development scientist shall perform drop test of filled shipper after vibration testing.

(b) (4) (b) (4) (b) (4)7.6 Hold the shipper at height as recommended in ASTM for weight ranging from kg and drop the shipper once on each faces as per below figure on flat rigid surface. Shipper Shape - Rectangular

(b) (4)Shipper Weight - Approx kgs

After vibration test, all the cartons to be checked for Visual Inspection for appearance, damage of the Carton, tray, Pen component, Cartridges, 3 ply shipper and 5 ply shipper. 9.2 After drop test, all the cartons to be checked for Visual Inspection for appearance, damage of the Carton, tray, Pen component, Cartridges, 3 ply shipper and 5 ply shipper. 9.3 To check physicochemical testing of test samples as per Annexure I. 9.4 To check the break out & glide force offtlled cartridges as per Annexure II.



Results: (b) (4)

(b) (4)

(b) (4)

(b) (4)

Conclusions/ Reviewer Comments:

The Shipping testing and protocol are not acceptable as they do not cover injection force. Also, the stability testing checked on 9/9/19 (manufactured in 2017). The follow-up IR above addresses the verification testing absence for injection force.

Acceptable: ☒Yes ☐No



8.2. Design Verification Review Conclusion

DESIGN VERIFICATION REVIEW CONCLUSION Filing Deficiencies: Yes No N/A



Reviewer Comments The verification testing is acceptable and covers ass EPRs, except for injection time, which is not covered, since it is variable. CDRH sent Design Verification Deficiency or Interactive Review Questions to the Sponsor: Yes No



Information Request #3


a. Additionally, you have not clarified whether your verification testing was performed with the final to-be-marketed version of the device. As part of design verification, you should verify the EPRs with the tobe-marketed version of the device constituent and the intended biologic/drug product. However, if you plan to rely on verification testing conducted with a surrogate (or different device design) be sure to provide a scientific rationale for the acceptability of the surrogate for the intended biologic/drug product (i.e. fluid characteristics, viscosity, etc.). If available, results of stability / shelf-life testing may be provided if the to-be-marketed version of the device constituent and intended drug/biologic product are used.

b. You have not provided a biocompatibility assessment of the device, including the material components, the manufacturing processes, the clinical use of the device including the intended anatomical location, and the frequency and duration of exposure. This information is required to ensure the device is safe. Please provide a justification or documentation to support the biocompatibility of your device constituent including test reports and protocols to ensure that the



system components are biocompatible commensurate with the level and duration of patient contact. Refer to the FDA Guidance titled Use of International Standard ISO 10993-1, "Biological evaluation of medical devices

- Part 1: Evaluation and testing within a risk management process" – Guidance for Industry and Food and Drug Administration Staff issued in June 2016 (https://www.fda.gov/media/85865/download) for more details.

Sponsor Response Please note that the Sun’s Octreotide pen injector device is manually operated, wherein user has to perform critical operating steps without any automated function. This pen injector is multi-use variable dose device unlike single use auto injector device which has automated mechanism for dose delivery.

Injection time test is relevant in case of auto injector or automated drug delivery. In pen injector device, time taken for delivery of required dose is dependent on the user as well as volume of the dose to be delivered. Once the dose set knob of the device is dialed to the required dose then user will push injection button all the way down to ensure that pointer on body sub-assembly aligns to “0” mark of the device. This entire step is done by user manually. There is no automated mechanism or component used in the device which will trigger the dose delivery automatically. Hence, injection time is not considered as the test during design verification test.

Please also note that in labeling user is instructed to hold the device for l 0 seconds (counts) even after injection button is completely pressed down to ensure he/she receives the dose completely.

a. Please note that design verification reports of both exhibit (wave I) (page# 119 of702) and commercial (wave 2) (page # 77 of 702) version of pens had been provided in section 3.2.P.7.2 of original NDA submission under leaf "Component Specification and Test Data". Delivered dose accuracy test is part of both design verification tests.

Other EPR test (break loose and glide force) is conducted on primary containers (3.0mL standard glass cartridge). There is no change in primary containers for exhibit batch and commercial version of pen components. As stated in Table 1.0, to-be marketed version is used for design verification and HF summative study. Design verification tests were conducted with saline water considering U1e fact that fluid properties (viscosity and density) of Octreotide acetate drug are similar to that of saline water. Report on equivalency of fluid properties has already been provided in section 3.2.P.7.2 of original N DA submission under leaf "Component Specification and Test Data " (page# 115 of 702).


(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)


b. Please note that device supplier has conducted the biocompatibility assessment of exhibit as well as commercial pen components. Please note that ISO compliance statement from device supplier for biocompatibility assessment for exhibit (wave I) as well as commercia l (wave 2) pen components has been provided herewith in Attachmen t 4. These tests are conducted as per ISO , "Biological evaluation of medical devices". Upon agency's requests, can provide detail protocols and reports directly to the agency.

Reviewer Comments The Sponsor provided a justification for not using injection time as an EPR. The Sponsor claims that injection time is not a relevant parameter, since it is variable with each dose setting and the amount of force applied by the user. This is acceptable since the injection time parameter is also indirectly controlled through dose accuracy testing (and partially through B/L and glide force release testing). The response is acceptable.

Biocompatibility was leveraged from has stated that they comply with ISO 10993 and a summary report of all in vitro and chemistry studies was provided. This is acceptable.

Response Adequate: Yes No, See IR # Sent on Click or tap to enter a date.

8.3. Discipline Specific Sub-Consulted Review Summary No Additional Discipline Specific Sub-Consults were requested

The following additional Discipline Specific Sub-Consults were requested:

9. CLINICAL VALIDATION REVIEW 9.1. Review of Clinical Studies Clinical Studies

There is no device related clinical studies for review There are clinical studies for review

10. HUMAN FACTORS VALIDATION REVIEW CDRH Human Factors Review conducted Human Factors deferred to DMEPA

11.FACILITIES & QUALITY SYSTEMS (Deferred to CDRH/OC) 11.1. Facility Inspection Report Review

CDRH Facilities Inspection Review conducted



CDRH Facilities Inspection Review was not conducted

11.2. Quality Systems Documentation Review CDRH Quality Systems Documentation Review conducted CDRH Quality Systems Documentation Review was not conducted

11.3. Control Strategy Review The Sponsor provided the following control strategy information regarding the EPRs of the device constituents:

Essential Performance Requirements Control Strategy Table * The proposed acceptance criteria for the EPR may be tighter than the design input and should be assessed for adequate quality control)/ Sampling Plan (Sampling plan may be review issue depending on the product (e.g. emergency-use)

Essential Performance Requirements

Control Strategy Description - The Sponsor provided the following description of how the essential performance requirements of the

combination product are controlled through incoming acceptance, in-process control, and/or release testing activities:

Acceptable (Y/N/NA)

Dose Accuracy

Release testing - Volume in container Not less than 3.1 ml. Delivered Dose Accuracy – for dose of 50, 100, and 200 mcg

Y

BL Force Release testing Y Glide Force Release testing Y Injection Time Not Provided – Justification provided – acceptable due to BL and glide

forces N/A

Injection Force

Release testing Y

Reviewer Comments

Th Sponsor’s approach is sufficient except for injection time, for which the Sponsor provided a justification interactively. Sample batch release specification and results for dose accuracy:

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

(b) (4)

Control Strategy Conclusion The Sponsor provided adequate information to support the manufacturing control activities for the essential performance requirements of the combination product. ☒Yes ☐No



11.4. Facilities & Quality Systems Review Conclusion (Deferred to OC)

FACILITIES & QUALITY SYSTEMS REVIEW CONCLUSION Filing Deficiencies: Yes No N/A



Reviewer Comments

CDRH sent Facilities & QS Deficiencies or Interactive Review Questions to the Sponsor: Yes No



12.APPENDIX A (INFORMATION REQUESTS) 12.1. Mid-Cycle Information Requests

2. In your Summary of Container Closure System, you provided a comparison between the “existing” and “commercial” versions of the pen injector and stated that “there is some minor changes to the secondary packaging components between the exhibit and propose commercial pen injector.” More information is necessary to ensure this change does not affect device function. Please clarify whether the design change affected any internal and/or mechanical components and which version(s) were used for all applicable device testing including the provided batch analyses, stability, and all clinical studies. If the testing you have performed used different versions, please provide a complete justification for each modification and whether it is expected to affect device performance, specifically, whether essential performance requirements (Dose Accuracy, Activation/Break loose/Glide Forces, Needle Length/Gauge) and other performance requirements (Ex. cap removal force) are affected.

a. Additionally, your device description is only provided in the Summary of Container Closure System and is missing information on several device characteristics. This information is required to ensure the device functions safely and effectively in the intended environment of use. Please provide a complete device description of the final finished device you intend to market. In your description, be sure to include pictures and/or diagrams of internal device components. A complete device description should also include (following aspects should be selected only if they apply to your device): the Injector/Platform Name, Specifications, Injection tissue and depth of injection, Audible / visual feedback, Cap Removal Force, Dose Accuracy, Activation Force, Visibility of medication container/Dose, Last Dose Specifications and Safety Features, Needle Specifications (Length(s), Gauge(s)), Connection type, Conformance to applicable standards, Type of Use (e.g. single use, disposable, reusable, other), Intended user (e.g., self-administration, professional use, user characteristics and / or disease state that impact device use), Injection mechanism (e.g., manual piston, spring, gas, etc.), Method of actuation, any Automated Functions, Residual Medication, Delivered Volume (for single dose or selectable volume range for multidose pens), Drug Container Type, Dose Units of Measure (e.g., mL, Units, mg, increments, etc.), Environments of use, Storage conditions and expiry, Graduation marks / fill lines, Preparation and administration (describe all that are applicable), Safety Features, Complete Material composition of injector, and other characteristics which may be applicable to your device. Please note if this information is provided elsewhere in the submission you may simply reference it.

3. You have not provided Risk Analysis Documentation. This information is necessary to ensure all risks associated with the device have been properly identified and mitigated. Please provide a risk analysis associated with the final finished combination product that is inclusive of risks associated with the device constituent parts of the combination product. Your risk analysis should include all identified risks, potential hazards that are apparent to your device, risk control measures and/or mitigation strategies, verification of risk control and/or mitigation measures, and the clinical acceptability of any residual risk associated with the device. You should outline the methods in which you identified the risks of the product within your risk analysis documentation (e.g. DFMEA, UFMEA, Fault Tree Analysis, etc.). Refer to recognized consensus standard ISO 14971 “Medical devices - Application of risk management to medical devices” or device specific Guidance for more details.




a. Additionally, you have not clarified whether your verification testing was performed with the final to-be-marketed version of the device. As part of design verification, you should verify the EPRs with the to-be-marketed version of the device constituent and the intended biologic/drug product. However, if you plan to rely on verification testing conducted with a surrogate (or different device design) be sure to provide a scientific rationale for the acceptability of the surrogate for the intended biologic/drug product (i.e. fluid characteristics, viscosity, etc.). If available, results of stability / shelf-life testing may be provided if the to-be-marketed version of the device constituent and intended drug/biologic product are used.

b. You have not provided a biocompatibility assessment of the device, including the material components, the manufacturing processes, the clinical use of the device including the intended anatomical location, and the frequency and duration of exposure. This information is required to ensure the device is safe. Please provide a justification or documentation to support the biocompatibility of your device constituent including test reports and protocols to ensure that the system components are biocompatible commensurate with the level and duration of patient contact. Refer to the FDA Guidance titled Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process" – Guidance for Industry and Food and Drug Administration Staff issued in June 2016 (https://www.fda.gov/media/85865/download) for more details.

12.2. Interactive Information Requests 12.2.1. Interactive Information Requests sent on 12/17/2019

1. There are outstanding device issues with your applications. We acknowledge you provided long term stability and shipping results which include break loose and glide forces. You also provided an 18-months stability report showing 2 units out of specification for lot JKSEX572. In your design control strategy, you also have elected to not perform testing of the injection force on the final finished device at worst case conditions (aging and shipping). Injection force is an essential performance requirement for the final finished device and verifies the users can inject the drug product up to the maximum labeled shelf life of the device. We recommend that you provide verification testing of the injection force for final finished device after aging and shipping. You may use a bracketed approach (min max dose) and you may define your acceptance criteria as an upper limit. Additionally, we recommend that you add injection force as a release specification for your batch release testing parameters. If you have existing force measurements collected during your dose accuracy testing, you may provide that granted you provide the complete methodology used and it is relevant to how your injector is used in a clinical setting. Also, since break loose and glide force is part of your control strategy in lieu of injection time testing, please explain the out of specification results in the 18-month stability testing.

RESPONSE (12/24/2019):


https://www.fda.gov/media/85865/download


Please note that based on agency's recommendation, Sun has conducted verification testing of the injection force on device after aging and shipping with maximum dose setting (200mcg). Average activation (injection) force test is based on glide force between cartridge and rubber stopper. Minimum dose setting (50mcg) has not been evaluated based on following considerations:

1) The travel distance of rubber stopper would be less than 2 mm in case of 50 meg dose setting. Data are recorded after initial dislodgement of the rubber stopper and also before alignment of "0" mark of dose set knob to the pointer on body sub-assembly. Therefore, for injection force measurement, rubber stopper has to travel minimum 2.5 mm distance at the beginning and shall stop at least 0.5mm before it reaches final position. The travel distance 2.5 mm is not available in 50 mcg dose setting.

2) Maximum dose setting has 4.5 mm as travelling distance for the rubber stopper which provides the worst-case scenario for injection force.

Sun has defined acceptance criteria as less than (b) (4)(b) (4) for average activation (injection) force based on design input specification (ERD 18-106 Rev 01) from the device supplier ( (b) (4)(b) (4)) provided in section 3.2.P.7.2 of original NDA submission. Sun has also developed method which is concurrent with the established method at device supplier to conduct average activation (injection) force test and it is in accordance with ISO

, (b) (4)(b) (4) 2012. In revised drug product release specification, test procedure, pre-approval stability protocol and post-

(b) (4)(b) (4)